The inability of non-human cells to support HIV-1 replication is due to the alteration of specific cell proteins. In the mouse, CD4 and cyclin T1 are altered such that they fail to interact with their respective partners, gp120 and Tat. Other critical cellular cofactors that remain to be identified are likely to be similarly altered. Heterokaryon experiments suggest that murine cells do not support HIV-1 assembly or release because they lack a putative species-specific cofactor. This project aims to identify this and other cellular cofactors that may be altered or nonfunctional in murine cells. This will be accomplished using a gene transfer approach in which human cDNAs are expressed in murine cells and screened for ability to support virus assembly and release. HIV-1 will also be adapted in culture to replicate in murine cells expressing the human cofactors. The adapted virus will be characterized and then used to infect transgenic mice. The immediate goal of the project is to gain increased understanding of virus-cell interactions. This information will be applied to develop a transgenic mouse model for AIDS. HIV-1 transmission by injection drug use accounts for 20 percent of domestic AIDS cases in the USA, amounting to 8,000 infections per year, and internationally accounts for 70 percent of new transmissions in parts of Eastern Europe. Development of a small animal model for AIDS will have multiple applications including the testing of anti-virals, vaccines and therapeutic strategies designed to prevent sexual and injection HIV-1 transmission. The specific aims are to: 1. Identify a human cofactor that facilitates HIV-1 replication in rodent cells. 2. Develop an HIV-1 variant able to replicate in-rodent cells. 3. Generate transgenic mice expressing the human cofactors and test them for ability to support HIV-1 replication.